EFFECTS OF ADRENERGIC AGONISTS AND ANTAGONISTS ON ADENYLATE CYCLASE ACTIVITY OF DOG HEART AND LIVER

¹ Department of Medicine, Division of Pharmacology, University of California, San Diego, La Jolla, California

The purpose of this investigation was to differentiate cardiac and hepatic adrenergic receptors iim terms of the response of adenylate cyclase to catecholamines and beta antagonists added to particulate preparations of the enzyme. Dissociation constants (K_B) for the heart preparation were 0.051 µM for propranolol and 56, 73 and 73 µM for butoxamine, isopropylmethoxamine and methoxamine, respectively. The K_B for an antagonist did not differ with each of the three catecholamine agonists used (isoproterenol, epinephrine and norepinephrine). The affinities for the liver enzyme preparations were much higher, K_B = 0.001 to 0.01 µM for propranolol and 1.7 to 4.0 µM for butoxamine, but these values varied with the agonist that was used. These data suggest a different type of beta receptor for these compounds in liver and heart. The higher potency of butoxamine in inhibiting adrenergic stimulation of liver adenylate cyclase provides an explanation for the observations made in vivo by other investigators, that methoxamine congeners blocked hepatic receptors more easily than the inotropic and biochemical responses of heart. The activation constants of catecholamines for cardiac adenylate cyclase were 275 to 660 times greater than the EC5O reported in time literature for these agents in stimulating cardiac contraction in vivo or in vitro. This discrepancy may reflect artifacts in the enzyme assay system, loss of sensitivity to stimulation after homogenization, or lack of dependence of augmentation of cardiac contraction on time activation of adenylate cyclase.